Methods for the preparation of indacaterol and pharmaceutically acceptable salts thereof

ABSTRACT

The invention relates to new and improved processes for the preparation of Indacaterol and pharmaceutically acceptable salts thereof as well as intermediates for the preparation of Indacaterol. The new process avoids the use of the epoxide compound known in the art and the impurities associated therewith and results in a higher yield.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of and claims the benefit and priorityto U.S. patent application Ser. No. 14/427,568, filed on Mar. 11, 2015,which is a U.S. National Phase application of PCT InternationalApplication Number PCT/EP2013/068618, filed on Sep. 9, 2013, designatingthe United States of America and published in the English language,which is an International Application of and claims the benefit ofpriority to International Patent Application No. PCT/EP2012/003961,filed on Sep. 21, 2012. The disclosures of the above-referencedapplications are hereby expressly incorporated by reference in theirentireties.

FIELD OF THE INVENTION

The present invention relates to new and improved processes for thepreparation of Indacaterol and pharmaceutically acceptable salts thereofas well as intermediates for the preparation of Indacaterol.

BACKGROUND OF THE INVENTION

The compound5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-(1H)-quinolin-2-one,which is known as Indacaterol (INN), and its corresponding salts arebeta-selective adrenoceptor agonists with a potent bronchodilatingactivity. Indacaterol is especially useful for the treatment of asthmaand chronic obstructive pulmonary disease (COPD) and is soldcommercially as the maleate salt.

WO 00/75114 and WO 2004/076422 describe the preparation of Indacaterolfor the first time through the process:

The condensation between the indanolamine and the quinolone epoxideleads to the desired product but always with the presence of asignificant amount of impurities, the most significant being the dimerimpurity, which is the consequence of a second addition of the productinitially obtained with another quinolone epoxide, as well as theformation of another isomer which is the result of the addition of theindanolamine to the secondary carbon of the epoxide.

In addition, the reaction conditions to achieve the opening of theepoxide require high energies (ex. 21 of WO 00/75114) with temperaturesof 110° C. or more for several hours, which favours the appearance ofimpurities.

WO 2004/076422 discloses the purification of the reaction mixture by theinitial formation of a salt with an acid, such as tartaric acid orbenzoic acid, hydrogenation and final formation of the maleate salt.However, the yield achieved by the end of the process is only 49%overall.

It has been found that impurities of tartrate and benzoate salts canexist in the final product as a result of displacing the tartrate orbenzoate with maleate without prior neutralization to Indacaterol base.In addition, WO 2004/076422 discloses that proceeding via the free baseof Indacaterol is not viable due to its instability in organic solvents.WO 00/75114 does disclose a method proceeding via the Indacaterol freebase, but it is not isolated in solid form.

WO 2004/076422 furthermore discloses the method for obtaining thequinolone epoxide from the corresponding α-haloacetyl compound byreduction in the presence of a chiral catalyst, such as anoxazaborolidine compound, by proceeding via the α-halohydroxy compound.

There exists, therefore, the need to develop an improved process forobtaining Indacaterol and salts thereof, which overcomes some or all ofthe problems associated with known methods from the state of the art.More particularly, there exists the need for a process for obtainingIndacaterol and pharmaceutically acceptable salts thereof, which resultsin a higher yield and/or having fewer impurities in the form of thedimer and regioisomers impurities and/or salts other than the desiredpharmaceutically acceptable salt.

SUMMARY OF THE INVENTION

In one aspect of the invention, it concerns a process for preparingIndacaterol or a pharmaceutically acceptable salt thereof comprisingreacting the compound of formula I with 2-amino-5,6-diethylindan offormula II, preferably in the presence of a base, to the compound offormula III and then converting the compound of formula III toIndacaterol or a pharmaceutically acceptable salt thereof:

wherein R¹ is a protecting group, R² is a protecting group, which isstable under mildly alkaline conditions, and X is a halogen selectedfrom the group consisting of chloro, bromo, and iodo.

This process avoids the formation of the dimers and regiostereoisomersassociated with the processes known in the art, e.g. in WO 2004/076422,since it avoids the use of the epoxy compound used in the prior artprocesses. This facilitates the purification of the compound of formulaIII, possible subsequent intermediates in the process, as well as thefinal product. The process of the invention furthermore has gentlerreaction conditions than the processes known in the art and results in ayield of more than 70% and in some cases more than 80%.

R¹ is a protecting group commonly known in the art for protecting phenolgroups. R² is a protecting group, which is stable under mildly alkalineconditions.

A further aspect of the invention concerns a process for the preparationof the compound of formula III or a salt thereof by reacting thecompound of formula I with 2-amino-5,6-diethylindan of formula II to thecompound of formula III. Optionally, the compound of formula III isconverted to a salt thereof by addition of an acid.

In another aspect of the invention, it concerns a process for thepreparation of a pharmaceutically acceptable salt of Indacaterol byobtaining Indacaterol, isolating it in solid form, and reacting it witha suitable acid, such as maleic acid.

Still another aspect of the invention concerns the compounds of formulaI. Yet another aspect of the invention concerns the compounds of formulaIII. A further aspect of the invention concerns Indacaterol free base insolid form.

DETAILED DESCRIPTION OF THE INVENTION Definitions

In the context of the present invention, the term “C₆₋₂₀ aryl” isintended to mean an optionally substituted fully or partially aromaticcarbocyclic ring or ring system with 6 to 20 carbon atoms, such asphenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracyl, phenanthracyl,pyrenyl, benzopyrenyl, fluorenyl and xanthenyl, among which phenyl is apreferred example.

In the context of the present invention, the term “C₁₋₆ alkyl” isintended to mean a linear or branched saturated hydrocarbon group havingfrom one to six carbon atoms, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl and n-hexyl.

In the context of the present invention, the term “C₁₋₆-alkoxy” isintended to mean C₁₋₆-alkyl-oxy, such as methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy,iso-pentoxy, neo-pentoxy and n-hexoxy.

In the context of the present invention, the term “C₂₋₆ alkenyl” isintended to cover linear or branched hydrocarbon groups having 2 to 6carbon atoms and comprising one unsaturated bond. Examples of alkenylgroups are vinyl, allyl, butenyl, pentenyl and hexenyl.

In the context of the present invention, the term “C₃₋₆ cycloalkyl” isintended to mean a cyclic hydrocarbon group having 3 to 6 carbon atoms,such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the context of the present invention, the term “heteroaryl” isintended to mean a fully or partially aromatic carbocyclic ring or ringsystem where one or more of the carbon atoms have been replaced withheteroatoms, e.g. nitrogen (═N— or —NH—), sulphur, and/or oxygen atoms.Examples of such heteroaryl groups are oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazinyl, coumaryl, furyl, thienyl, quinolyl,benzothiazolyl, benzotriazolyl, benzodiazolyl, benzooxozolyl,phthalazinyl, phthalanyl, triazolyl, tetrazolyl, isoquinolyl, acridinyl,carbazolyl, dibenzazepinyl, indolyl, benzopyrazolyl, phenoxazonyl,phenyl pyrrolyl and N-phenyl pyrrolyl.

In the present context, the term “optionally substituted” is intended tomean that the group in question may be substituted one or several times,preferably 1-3 times, with group(s) selected from hydroxy (which whenbound to an unsaturated carbon atom may be present in the tautomericketo form), C₁₋₆-alkoxy, C₂₋₆-alkenyloxy, carboxy, oxo (forming a ketoor aldehyde functionality), C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyl,formyl, aryl, aryloxycarbonyl, aryloxy, arylamino, arylcarbonyl,heteroaryl, heteroarylamino, heteroaryloxycarbonyl, heteroaryloxy,heteroarylcarbonyl, amino, mono- and di(C₁₋₆-alkyl)amino, carbamoyl,mono- and di(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl,mono- and di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl,C₁₋₆-alkylcarbonyl amino, cyano, guanidino, carbamido,C₁₋₆-alkyl-sulphonyl-amino, aryl-sulphonyl-amino,heteroaryl-sulphonyl-amino, C₁₋₆-alkanoyloxy, C₁₋₆-alkyl-sulphonyl,C₁₋₆-alkyl-sulphinyl, C₁₋₆-alkylsulphonyloxy, nitro, C₁₋₆-alkylthio andhalogen.

In the present context, the term “mildly alkaline conditions” refers toconditions created when adding the compound of formula II, which is abase, to the compound of formula I, preferably in the presence of afurther base, such as triethylamine, diisopropylethylamine (DIPEA),pyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 4-dimethylaminopyridine(DMAP), sodium carbonate, potassium carbonate, sodium hydrogencarbonate,potassium hydrogencarbonate, sodium hydroxide, or potassium hydroxide.

Processes

In one aspect of the invention, it concerns a process for preparingIndacaterol or a pharmaceutically acceptable salt thereof comprisingreacting the compound of formula I with 2-amino-5,6-diethylindan offormula II, preferably in the presence of a base, to the compound offormula III and then converting the compound of formula III toIndacaterol or a pharmaceutically acceptable salt thereof:

wherein R¹ is a protecting group, R² is a protecting group, which isstable under mildly alkaline conditions, and X is a halogen selectedfrom the group consisting of chloro, bromo, and iodo.

In one embodiment, the compound of formula III is converted toIndacaterol by first converting it to a compound of formula IV by firstremoving the protecting group R² by addition of an acid, preferably anaqueous acid, and finally isolating/purifying the compound (IV) as asalt by adding the acid HA:

and then converting the compound of formula IV to Indacaterol or apharmaceutically acceptable salt thereof. Processes for converting thecompound of formula IV to Indacaterol or a pharmaceutically acceptablesalt thereof are disclosed inter alia in WO 2004/076422.

In a further embodiment, the compound of formula IV is converted toIndacaterol or a pharmaceutically acceptable salt thereof by:

-   -   a) neutralizing the compound of formula IV, removing the        protecting group R¹ to obtain Indacaterol free base in solution        or suspension, optionally isolating Indacaterol free base in        solid form, and, optionally, obtaining a pharmaceutically        acceptable salt of Indacaterol by addition of a suitable acid,        such as maleic acid, to the free base;    -   b) removing the protecting group R¹ to obtain a compound of        formula V:

-   -    neutralizing the compound of formula V to obtain the free        Indacaterol base in solution or suspension, optionally isolating        Indacaterol free base in solid form, and, optionally, obtaining        a pharmaceutically acceptable salt of Indacaterol by addition of        a suitable acid, such as maleic acid, to the free base; or    -   c) removing the protecting group R¹ to obtain a compound of        formula V, reacting the compound of formula V directly with a        suitable acid, such as maleic acid, to obtain a pharmaceutically        acceptable salt of Indacaterol.        The Compound of Formula III

The compound of formula III may be isolated as the free base or throughthe formation of an acid addition salt without removing the protectinggroup R² or used directly without isolating it in the furtherpreparation of Indacaterol or a pharmaceutically acceptable saltthereof, such as proceeding via the compound of formula IV.

R¹ Protecting Groups

R¹ is a protecting group commonly known in the art for protecting phenolgroups. The skilled person will be aware of suitable protecting groupsfor hydroxy groups in the 8-position of quinolone derivatives such asthe compound of formula I. Such suitable protecting groups may be foundin WO 00/75114 and WO 2004/076422.

More particularly, in one embodiment, R¹ is selected from the groupconsisting of a C₁₋₆ alkyl, C₆₋₂₀ aryl, C₁₋₆-alkoxy, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, benzocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₆₋₂₀ aryl-C₁₋₆alkyl, heteroaryl, heteroaryl-C₁₋₆ alkyl, halo-C₁₋₆ alkyl, and anoptionally substituted silyl group. In another embodiment, R¹ is benzylor t-butyldimethylsilyl. In yet another embodiment, R¹ is benzyl.

R² Protecting Groups

R² is a protecting group, which is stable under mildly alkalineconditions and which can be cleaved off selectively under conditionswhere R¹ is not cleaved off. A number of protecting groups fulfil thesecriteria, including, but not limited to, protecting groups forming anacetal together with the adjacent oxygen atom, protecting groups formingan ether together with the adjacent oxygen, protecting groups forming asilyl ether group with the adjacent oxygen, and protecting groupsforming an ester together with the adjacent oxygen. Hence, in oneembodiment, R² forms an acetal, an ether, a silyl ether, or an estertogether with the adjacent oxygen. In another embodiment, R² forms anacetal, an ether, or a silyl ether together with the adjacent oxygen. Inyet another embodiment, R² forms an acetal or an ether together with theadjacent oxygen. In a further embodiment, R² forms an acetal togetherwith the adjacent oxygen.

Examples of suitable acetal protecting groups are 1-(n-butoxy)-ethylacetal and tetrahydro-pyran-2-yl acetal. Thus, in one embodiment, R² is1-(n-butoxy)-ethyl or tetrahydro-pyran-2-yl, such as 1-(n-butoxy)-ethyl.Examples of suitable ether protecting groups are benzyl ether,methoxymethyl (MOM) ether, methylthiomethyl (MTM) ether, andbenzyloxymethyl ether. Thus, in another embodiment, R² is benzyl,methoxymethyl, methylthiomethyl, or benzyloxymethyl, such as benzyl.Examples of suitable silyl ether protecting groups are trimethylsilylether and tert-butyldimethylsilyl ether. Thus, in still anotherembodiment, R² is trimethylsilyl or tert-butyldimethylsilyl. Examples ofsuitable ester protecting groups are pivaloyl ester and acetate ester.Thus, in yet another embodiment, R² is pivaloyl or acetate.

In a further embodiment, R² is selected from the group consisting of1-(n-butoxy)-ethyl, methoxymethyl, benzyl, and tetrahydro-pyran-2-yl,such as from the group consisting of 1-(n-butoxy)-ethyl, methoxymethyl,and tetrahydro-pyran-2-yl. In yet a further embodiment, R² is1-(n-butoxy)-ethyl and R¹ is benzyl.

Methods for Removing the Protecting Group R²

The protecting group R² may be removed from the compound of formula IIIby methods known in the art for the various R² protecting groups definedherein. In the case of R² forming an acetal together with the adjacentoxygen atom, R² may be removed by reacting with an intermediate tostrong acid, preferably in the presence of water. Examples of suitableacids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, phosphoric acid, camphorsulfonic acid, methanesulfonic acid,trifluoromethanesulfonic acid, and combinations thereof.

In the case of R² forming an ether, silyl ether, or ester together withthe adjacent oxygen atom, the acids mentioned for the acetal protectinggroups are also suitable for removing R². Other suitable agents forremoving R² in the case of R² forming an ether, silyl ether, or estertogether with the adjacent oxygen atom are aqueous bases, lewis acids,hydrogen over palladium or platinum catalyst (in the case of benzylether), resins such as Dowex, thiols such as thiophenol, andcombinations thereof.

Bases Useful in the Reaction of Compounds I and II

Any organic or inorganic base may be employed in the reaction betweencompounds I and II in the formation of the compound of formula III, withthe exception of primary and secondary amines. Examples of usefulorganic bases in this reaction are triethylamine, diisopropylethylamine(DIPEA), pyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), and4-dimethylaminopyridine (DMAP). Examples of useful inorganic bases inthis reaction are sodium carbonate, potassium carbonate, sodiumhydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, andpotassium hydroxide. When carrying out the reaction between thecompounds of formula I and II in the presence of a base, the2-amino-5,6-diethylindan of formula II may be added to the reactionmixture in the form of an acid addition salt thereof, such as thehydrochloride salt thereof.

The Acid HA

Reacting the product obtained by removing the protecting group R² fromthe compound of formula III with the acid HA serves to purify thecompound by obtaining the salt of formula IV. Examples of suitable HAacids are benzoic acid, maleic acid, fumaric acid, succinic acid,tartaric acid, hydrochloric acid, hydrobromic acid, dibenzoyl-tartaricacid, mandelic acid, and camphorsulfonic acid.

In one embodiment, the acid HA is selected from the group consisting oftartaric acid, dibenzoyl-tartaric acid, mandelic acid, succinic acid,and benzoic acid. In another embodiment, the acid HA is selected fromthe group consisting of tartaric acid, succinic acid, and benzoic acid.

The Halogen X

Halogens generally constitute good leaving groups in an S_(N)2-typereaction, such as the reaction between the compounds of formula I andII. In one embodiment, X is selected from the group consisting ofchloro, bromo, and iodo. In another embodiment, X is bromo or iodo. Inyet another embodiment, X is bromo.

In a further embodiment, X is bromo or chloro and the reaction betweencompounds I and II takes place in the presence of an iodine salt, suchsodium iodide or potassium iodide, which generates the iodo group insitu.

The Starting Compound of Formula I

The compound of formula I may be obtained from the correspondinghydroxy-unprotected compound of formula VI:

by reacting with the reagents known in the art to form the acetal,ether, silyl ether, or ester protecting groups defined herein whenreacted with an alcohol. In the case of e.g. acetal protecting groups,in the case where R² is 1-(n-butoxy)-ethyl or tetrahydro-pyran-2-yl, thecompound of formula VI may be reacted with butyl-vinyl ether ordihydro-pyran-2-yl, respectively.

The compound of formula VI may be prepared by reducing the correspondinghaloacetyl compound using a chiral catalyst. Suitable chiral catalystsfor this method are disclosed in WO 2004/076422 and WO 2005/123684, thecontents of which are incorporated in their entirety herein.

Pharmaceutically Acceptable Salts

Pharmaceutically acceptable acid addition salts of Indacaterol areeasily identified by the skilled person. A useful list ofpharmaceutically acceptable acid addition salts may be found in Berge etal: “Pharmaceutical Salts”, Journal of Pharmaceutical Sciences, vol. 66,no. 1, 1 Jan. 1977, pages 1-19. A particularly interestingpharmaceutically acceptable acid addition salt is the maleate salt.

Proceeding Via Indacaterol Base

As discussed above, Indacaterol free base is known in the art to beunstable in organic solvents. Hence, preparing pharmaceuticallyacceptable salts of Indacaterol by proceeding via the free Indacaterolbase is not considered viable on an industrial scale. It has, however,been found that by isolating the free base in solid form,pharmaceutically acceptable salts of Indacaterol may indeed be preparedon an industrial scale by proceeding via the free Indacaterol base.Furthermore, this avoids the impurities associated with the methodsknown in the art for converting one salt of 8-protected Indacateroldirectly to a pharmaceutically acceptable salt of Indacaterol. Example 2of WO 2004/076422 was reproduced, hydrogenating the benzoate salt offormula IV using acetic acid as the solvent, and then exchanging theanion of the salt to maleate by addition of maleic acid. The obtainedsolid was filtered, washed, and dried in vacuum to give the Indacaterolmaleate with impurities of Indacaterol acetate as measured by NMR(Comparative example 9).

Thus, in another aspect of the invention, it concerns a process for thepreparation of a pharmaceutically acceptable salt of Indacaterol byobtaining Indacaterol, isolating it in solid form, and reacting it witha suitable acid, such as maleic acid. Indacaterol free base may beobtained as disclosed herein or as known in the art.

Useful Reaction Conditions

Formation of the Compound of Formula III

The reaction may take place in a number of different organic solvents.Useful examples are acetonitrile, butanone, and dimethylformamide (DMF),in particular acetonitrile and butanone. It has been found advantageousto use small volumes of solvent in the reaction between the compounds offormula I and II. The reaction is advantageously carried out at atemperature in the range of 70 to 110° C., such as at 85° C., with aduration of between 2 and 10 hours, such as 4 to 5 hours. Furthermore,when adding the 2-amino-5,6-diethylindan of formula II as an acidaddition salt thereof, a carbonate salt, such as potassium carbonate, isadvantageously added to the reaction mixture.

Removing the Protecting Group R²

When using an aqueous acid for removing the protecting group R², e.g.1-(n-butoxy)-ethyl, from the compound of formula III said acid, such ashydrochloric acid, is advantageously added in excess, such as 2 to 6equivalents, at a temperature between room temperature and reflux untilcomplete removal of the protecting group, e.g. 1 to 3 hours for removingthe 1-(n-butoxy)-ethyl protecting group.

Formation of the Compound of Formula IV

Once the protecting group R² has been removed, more water mayadvantageously be added together with a suitable solvent, such asdichloromethane. The deprotected compound may be neutralized at a pH of9 to 11 and the resulting phases then separated. After separation, thesolvent may be changed to a solvent suitable for precipitation of thecompound of formula IV. Useful solvents are ethyl acetate, isopropanol,ethanol, acetone, tetrahydrofuran, and acetonitrile, ethyl acetate,isopropanol, and ethanol currently being more preferred. After changingthe solvent, the acid HA may be added to form the compound of formula IVby precipitation. Ethyl acetate is a particularly useful solvent forprecipitating the benzoate, succinate, and tartrate salts. The salt offormula IV may be obtained with a yield of 65 to 80% and a purity ofgreater than 93%% in the case of tartrate precipitated in ethyl acetate,and a yield of 60 to 75% and a purity of greater than 99% in the case ofsuccinate and tartrate precipitated in isopropanol or ethanol. Theabsence of dimer and regioisomer impurities as known in the artfacilitates a more quantitative precipitation using ethyl acetate sincethere is no competition for the base molecules.

Formation of Indacaterol Base

The compound of formula IV may be neutralized before deprotection of R¹.The neutralization may suitably be achieved by addition ofdichloromethane, water and soda. When R¹ is removed by hydrogenation, itmay suitably be achieved using an overpressure of hydrogen at ambienttemperature. Furthermore, a mixture of methanol and dichloromethane asthe solvent is suitably employed in the process. Upon completion of thehydrogenation, the catalyst is removed and dichloromethane is distilledoff to leave methanol as the only solvent, which causes Indacaterol toprecipitate upon cooling. Alternatively, the methanol/dichloromethanemixture is exchanged with isopropanol solvent, which is cooled toachieve precipitation of Indacaterol base with a purity of >99%.

Precipitated Indacaterol base is a white solid, which may be stored atambient temperature for extended periods of time. Upon dissolution itmay be used to prepare a pharmaceutically acceptable salt, such as themaleate salt. A suitable solvent for the addition of maleic acid isisopropanol. Alternatively, Indacaterol base obtained from the reactionand dissolved in a mixture of methanol and dichloromethane can be useddirectly, the solvent exchanged for isopropanol, and then precipitatedas the maleate salt by adding maleic acid.

Intermediate Compounds

The process of the invention involves novel intermediates, which havenot previously been used in the preparation of Indacaterol. Hence, afurther aspect of the invention concerns the compounds of formula I. Yetanother aspect of the invention concerns the compounds of formula III,or salts thereof.

A further aspect of the invention concerns Indacaterol free base insolid form. In one embodiment, said Indacaterol free base is incrystalline form. In another embodiment, said Indacaterol free base isin amorphous form.

EXAMPLES Example 1—Protecting the α-Halohydroxy Compound of Formula VI

A flask was charged with 5 ml of tetrahydrofuran (THF) and 5 ml oftoluene. p-toluene sulfonic acid (0.15 mmol) and molecular sieves wereadded with stirring for 30 minutes. 6 mmol of butyl-vinylether and 3mmol of8-(phenylmethoxy)-5-((R)-2-bromo-1-hydroxy-ethyl)-(1H)-quinolin-2-onewere added. The mixture was agitated at 20/25° C. until completion ofthe reaction, followed by filtration and distillation of the filtrate toremove the solvent. The product is obtained in quantitative yield as anoil consisting of 50% of each of the diastereomers.

¹H-NMR (DMSO-d6, δ), mixture 50/50 of diastereomers: 0.61 and 0.82 (3H,t, J=7.2 Hz, CH₃—Pr—O), 1.12 and 1.22 (3H, d, J=5.6 Hz, acetalic CH₃),0.90-1.40 (4H, m, CH₂+CH₂), 3.20-3.80 (4H, m, CH₂—OAr+CH₂—Br), 4.51 and4.82 (1H, q, J=5.6 Hz, acetalic CH), 5.18 and 5.24 (1H, dd, J=4.0, 8.0Hz, CH—O-acetal), 6.56 and 6.58 (1H, d, J=10.0 Hz, H4), 7.00-7.57 (7H,m), 8.17 and 8.23 (1H, d, J=10.0 Hz, H3), 10.71 (1H, s, NH)

¹³C-NMR (DMSO-d6, δ), mixture 50/50 of diastereoisomers: 13.5 and 13.7CH₃), 18.5 and 18.8 (CH₂), 19.9 and 20.0 (acetalic CH₃), 30.9 and 31.4(CH₂), 36.8 and 37.3 (CH₂), 63.7 and 64.2 (CH₂—Br), 69.8 and 69.9(CH₂—OAr), 73.8 and 75.1 (CH—O), 97.5 and 100.4 (acetalic CH), 111.8(CH), 116.9 and 117.2 (C), 121.2 and 122.4 (CH), 122.3 and 122.6 (CH),127.7 and 127.8 (C), 127.8 and 127.9 (CH), 128.2 and 128.3 (CH), 128.8and 129.1 (C), 129.4 and 129.6 (C), 136.1 and 136.5 (CH), 136.5 and136.6 (C), 144.0 and 144.2 (C), 160.7 and 160.8 (C═O).

Example 2—Protecting the α-Halohydroxy Compound of Formula VI

Pivaloyl chloride (0.72 g) was added to a stirred mixture of8-(phenylmethoxy)-5-((R)-2-chloro-1-hydroxy-ethyl)-(1H)-quinolin-2-one(0.74 g), dichloromethane (15 ml) and 4-dimethylaminopyridine (0.89 g)at 20/25° C., and the reaction was stirred until all the startingmaterial disappeared. Water (22 ml) was added and the phases wereseparated.

The organic phase was washed with 1 M HCl (22 ml) and then with water(22 ml). The solvent was removed and the residue was crystallized fromacetone to obtain 0.82 g of the product.

¹H-NMR (DMSO-d6, δ): 1.13 (9H, s, CH₃), 3.92 (1H, dd, J=4.0, 12.0 Hz,CH₂—Br), 4.00 (1H, dd, J=8.4, 12.0 Hz, CH₂—Cl), 5.28 (2H, s, Ph-CH₂—O),6.25 (1H, dd, J=4.0, 8.4 Hz, CH—OPiv), 6.59 (1H, d, J=10.0 Hz, H4), 7.15(1H, d, J=8.4 Hz, H6), 7.20 (1H, d, J=8.4 Hz, H7), 7.27-7.30 (1H, m,Ph), 7.33-7.37 (2H, m, Ph), 7.54-7.56 (2H, m, Ph), 8.18 (1H, d, J=10.0Hz, H3), 10.77 (1H, s, NH).

¹³C-NMR (DMSO-d6, δ): 26.7 (3×CH₃), 38.3 (C), 46.4 (CH₂—Cl), 69.8(CH₂-Ph), 71.3 (CH—OPiv), 111.9 (CH), 116.8 (C), 120.5 (CH), 122.9 (CH),126.0 (C), 127.8 (2×CH), 127.9 (CH), 128.3 (2×CH), 129.5 (C), 136.0 (C),136.5 (CH), 144.5 (C), 160.7 (CON), 176.2 (COO).

Example 3—Preparation of the Compound of Formula IV

A flask was charged with 2.5 ml of THF and 2.5 ml of toluene. p-toluenesulfonic acid (5 mg) and molecular sieves (0.2 g) were added withstirring for 30 minutes. 1.5 ml of butyl-vinylether and 2 g of8-(phenylmethoxy)-5-((R)-2-bromo-1-hydroxy-ethyl)-(1H)-quinolin-2-onewere added. The mixture was agitated at 20/25° C. until completion ofthe reaction. 0.015 ml of diisopropylethyl amine was added, the mixturewas filtered, and the solvent was distilled off.

The residue was dissolved in 6 ml of dimethylformamide (DMF), 1.9 ml ofdiisoproypylethyl amine, 1.2 g sodium iodide, and 1.5 g of2-amino-5,6-diethylindane were added and the mixture was heated to 100°C. After completion of the reaction the mixture was cooled to 20/25° C.,0.4 ml of concentrated hydrochloric acid and 0.4 ml of water were added,and the mixture was stirred for 30 minutes.

HPLC analysis showed the expected product with a purity of 75% and beingfree from the dimer and regioisomer impurities.

20 ml of water, 20 ml of methylene chloride, and 3 ml of 6N NaOH wereadded with stirring. The organic phase was separated and washed with 20ml of water. The organic phase was distilled and the solvent was changedto ethyl acetate with a final volume of 100 ml. The mixture was heatedto 70° C., 0.8 g of L-tartaric acid was added, and stirring continuedfor 30 minutes at 70° C. The mixture was cooled slowly to 20/25° C.,filtered, and washed with 8 ml of ethyl acetate to obtain8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-(1H)-quinolin-2-onetartrate in 68% yield. The purity of the product was >95% by HPLCanalysis.

Example 4—Preparation of the Compound of Formula IV

A flask was charged with 19 ml of THF and 19 ml of toluene. p-toluenesulfonic acid (75 mg) and molecular sieves (1.5 g) were added and themixture was stirred for 30 minutes. 11.2 ml of butyl-vinylether and 15 gof 8-(phenylmethoxy)-5-((R)-2-bromo-1-hydroxy-ethyl)-(1H)-quinolin-2-onewere added. The mixture was agitated at 20/25° C. until completion ofthe reaction. 0.1 ml of diisopropylethyl amine were added, the mixturewas filtered, and the solvent was distilled off.

The residue was dissolved in 40 ml of butanone, 14.5 ml ofdiisoproypylethyl amine, 9 g sodium iodide, and 11.3 g of2-amino-5,6-diethylindane were added and the mixture was heated to90-100° C. After completion of the reaction the mixture was cooled to20/25° C., 3 ml of concentrated hydrochloric acid and 3 ml of water wereadded, and the mixture was stirred for 30 minutes.

HPLC analysis showed the expected product with a purity of 84% and beingfree from the dimer and regioisomer impurities.

150 ml of water, 150 ml of methylene chloride, and 22.5 ml of 6N NaOHwere added with stirring. The organic phase was separated and washedwith 10 ml of water. The organic phase was distilled and the solvent waschanged to isopropyl alcohol with a final volume of 300 ml. The mixturewas heated to 70° C., 4.9 g of benzoic acid was added, and stirringcontinued for 30 minutes at 70° C. The mixture was cooled slowly to20/25° C., filtered, and washed with 30 ml of isopropanol to obtain8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-(1H)-quinolin-2-onebenzoate in 59% yield. The purity of the product was >99% by HPLCanalysis.

Example 5—Preparation of the Compound of Formula IV

A flask was charged with 7.5 ml of THF and 7.5 ml of toluene. p-toluenesulfonic acid (30 mg) and molecular sieves (0.6 g) were added and themixture was stirred for 30 minutes. 4.5 ml of butyl-vinylether and 6 gof 8-(phenylmethoxy)-5-((R)-2-bromo-1-hydroxy-ethyl)-(1H)-quinolin-2-onewere added. The mixture was agitated at 20/25° C. until completion ofthe reaction. 0.040 ml of diisopropylethyl amine were added, the mixturewas filtered, and the solvent was distilled off.

The residue was dissolved in 18 ml of acetonitrile (ACN), 5.8 ml ofdiisoproypylethyl amine, 3.6 g sodium iodide, and 4.5 g of2-amino-5,6-diethylindane were added and the mixture was heated to80-90° C. After completion of the reaction the mixture was cooled to20/25° C., 1.2 ml of concentrated hydrochloric acid and 1.2 ml of waterwere added, and the mixture was stirred for 30 minutes. HPLC analysisshowed the expected product with a purity of 89% and being free from thedimer and regioisomer impurities.

60 ml of water, 60 ml of methylene chloride, and 9 ml of 6N NaOH wereadded with stirring. The organic phase was separated and washed with 60ml of water. The organic phase was distilled and the solvent was changedto isopropyl alcohol with a final volume of 120 ml. The mixture washeated to 70° C., 1.9 g of succinic acid was added, and stirringcontinued for 30 minutes at 70° C. The mixture was cooled slowly to20/25° C., filtered, and washed with 12 ml of isopropanol to obtain8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-(1H)-quinolin-2-onesuccinate in 56% yield. The purity of the product was >99% by HPLCanalysis.

Example 6—Preparation of Indacaterol Maleate

28 g of8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-(1H)-quinolin-2-onetartrate was dissolved in a mixture of 560 ml of dichloromethane, 560 mlof water, and 30 ml of an aqueous solution of 6N sodium hydroxide understirring. The phases were separated and the organic phase was washedwith 280 ml of water.

The organic phase was distilled to a final volume of 140 ml and 420 mlof methanol and 4.2 g of Pd/C (5%-50% water) were added. The system waspurged with nitrogen and subsequently with hydrogen at an overpressureof 0.3 bar and stirring until completion of the reaction.

The catalyst was filtered off and the solvent was changed to isopropanoladjusting the final volume to 950 ml. The solution was heated to 70/80°C. and a solution of 5.4 g maleic acid in 140 ml of isopropanol wasadded, maintaining the temperature between 70 and 80° C. The mixture wasstirred at 70/80° C. for 30 minutes and then slowly cooled to 20/25° C.The resulting suspension was filtered, the solid residue was washed with90 ml of isopropanol and dried to obtain 18 g of Indacaterol maleate(Yield: 79%). The product showed 99.6% purity by HPLC analysis.

Example 7—Isolation of Indacaterol Free Base in Solid Form

1 g of8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-(1H)-quinolin-2-onetartrate was dissolved in a mixture of 20 ml of dichloromethane, 20 mlof water, and 1 ml of an aqueous solution of 6N sodium hydroxide understirring. The phases were separated and the organic phase was washedwith 10 ml of water.

The organic phase was distilled to a final volume of 5 ml and 15 ml ofmethanol and 0.15 g of Pd/C (5%-50% water) were added. The system waspurged with nitrogen and subsequently with hydrogen at an overpressureof 0.3 bar and stirring until completion of the reaction.

The catalyst was filtered off and the solvent was changed to isopropanoladjusting the final volume to 8 ml. The resulting suspension was cooledto 0-5° C., filtered and the solid residue was washed with isopropanoland dried to obtain 0.47 g of Indacaterol free base (77%) showing 99.6%purity by HPLC analysis.

A sample of Indacaterol free base stored at 20-25° C. was analysed onemonth later without showing any loss of purity.

Example 8—Obtaining the Maleate Salt from Indacaterol Free Base

0.47 g of solid Indacaterol were suspended in 20 ml of isopropanol,heated to 70/80° C., and a solution of 0.15 g of maleic acid in 5 ml ofisopropanol were added, maintaining the temperature between 70 and 80°C. The mixture was cooled to 0/5° C. and filtration of the resultingsolid afforded 0.52 g of Indacaterol maleate with a purity of 99.7%.

Comparative Example 9—Direct Conversion to Indacaterol Maleate

8-(phenylmethoxy)-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-(1H)-quinolin-2-onebenzoate (4 g) was dissolved in acetic acid (40 ml). Pd/C (5%, 50% wet,0.6 g) was added and the product was hydrogenated under a hydrogenatmosphere. When the reaction was complete the catalyst was filtered offand the filtrate was vacuum distilled until a volume of 8 ml wasreached.

Ethanol (40 ml) was added and the mixture was heated to 50° C. Asolution of 1.2 g of maleic acid in 2.4 ml of ethanol was added and themixture was seeded with indacaterol maleate and then slowly cooled to0/5° C. The solid was filtered and washed with 5 ml of ethanol and 3 mlof isopropanol to obtain 6.0 g of indacaterol maleate.

1H-NMR analysis of the solid showed the presence of acetic acid in 2-4%by integration of the peak at δ 1.88 (400 MHz, DMSO-d6) corresponding toacetic acid.

The invention claimed is:
 1. Indacaterol free base in solid form,wherein said Indacaterol free base is in crystalline form.